Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To identify genetic changes related to tumor progression and find out diagnostic and prognostic genetic markers in gastrointestinal stromal tumors (GISTs), 95 tumor samples (24 benign GISTs, 36 malignant primary GISTs, and 35 GIST-metastases) from 60 patients were studied using comparative genomic hybridization. DNA copy number changes were detected in all samples. Benign GISTs had a mean of 2.6 aberrations/ sample (losses:gains, 5:1) and significantly fewer DNA copy number changes and fewer gains than malignant primary and metastatic GISTs (P < 0.01). High-level amplifications were not seen in benign GISTs. Malignant primary GISTs had a mean of 7.5 aberrations/tumor (losses: gains, 1.6:1), whereas the mean number of aberrations/metastatic GIST was 9 (losses:gains, 1.8:1). Frequent changes observed in all GIST groups included losses in chromosome arms 1p (51%), 14q (74%), and 22q (53%). Gains and high-level amplifications at 8q and 17q were significantly more frequent in metastatic GISTs (57 and 43%) than in benign GISTs (8 and 0%; P < 0.001) and malignant primary GISTs (33 and 25%; P < 0.05). Gains and high-level amplifications at 20q were only seen in malignant primary and metastatic GISTs (P < 0.01), and gains at 5p were not detected in benign GISTs (P < 0.01). Losses in chromosome arm 9p were never seen in benign tumors (P < 0.001), and they were more frequent in metastatic GISTs than in malignant primary GISTs (63 and 36%; P < 0.05). Losses in 13q were less frequent in benign GISTs than in malignant primary (P < 0.05) and metastatic (P < 0.01) GISTs. Our results show that several DNA copy number changes are related to the behavior of GISTs and can be used as prognostic markers for tumor progression.
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PMID:DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance. 1091 66

The Authors, after a short review of small bowel tumors, point out that recently a laparoscopic approach for these tumors has been suggested and some cases have been reported. The Authors present two cases of patients operated for small bowel tumor using a laparoscopic technique: the first case for a stromal tumor (GIST), the second case for an adenocarcinoma in advanced stage with multilobar lung metastases. The first patient is alive and disease free after one year, the second died after six months for tumor progression. The Authors believe that laparoscopic technique can be employed with satisfying results also in the treatment of small bowel tumors with moderate trauma and invasiveness.
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PMID:[Surgical laparoscopic therapy of small bowel tumors: review of the literature and report of two cases]. 1555 86

Serological analysis of recombinant cDNA libraries (SEREX) uses high titer IgGs to identify antigens expressed by autologous cancers. In order to identify tumor antigens in soft tissue sarcoma (STS), sera from four patients with malignant fibrous histiocytoma (MFH), gastrointestinal stromal tumor (GIST), pleomorphic liposarcoma, and dedifferentiated liposarcoma were screened against cDNA libraries derived from autologous tumor. We identified 18 antigens encoded by 15 different genes, including DLG7, which is located on chromosome 14q22, a locus previously found to be altered in STS, and the proto-oncogene JUN. Ten of fourteen antigens (71%) do not react with sera from healthy donors, suggesting that antibody recognition takes place during cancer progression. Using oligonucleotide microarray technology, most genes were variably expressed across a panel of 16 benign specimens and 41 STSs of different histologies. DLG7, however, showed restricted expression in testes and cancer, similarly to known germ cell cancer-testis antigens (or germ cell antigens, GCAs). Thus, the current study identified several antigens, including molecules implicated in tumorigenesis that were recognized by high titer IgGs in STS patients. Further studies of these selected novel STS antigens are warranted to identify and characterize potential antigen targets expressed by STS.
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PMID:Antigens recognized by autologous antibodies of patients with soft tissue sarcoma. 1574 19

The term "targeted cancer therapies" refers to treatment strategies designed to inhibit the product of an oncogene involved in the process of neoplastic transformation. Different categories of targeted therapies can be identified: 1) Therapies directed at oncogenes that are directly involved in the initiation of neoplastic transformation: the use of imatinib for the treatment of CML or GIST is the classical model in this subgroup. Single agent targeted therapies generally produce high response rates in this situation. 2) Therapies directed at oncogenes involved at a later stage of neoplastic transformation. These oncogenes contribute to tumor progression but not necessarily to the onset of malignant transformation. The use of trastuzumab for HER2-amplified breast adenocarcinoma is the classical model in this subgroup. These treatments are associated with low response rates when used as single agent therapy, whereas generally displaying a synergistic or additive effect with classical chemotherapy in models currently available. In contrast, when these targeted therapies are applied to tumor models where the targeted gene is present but not directly involved in the process of malignant transformation, no antitumor efficacy is generally observed. Recently, the identification of HER1 mutations in subsets of lung carcinoma as a predictive factor for response to gefitinib and erlotinib provided an example of how the empiric use of a targeted treatment may enable to identify new nosological entities. The present paper reviews examples of targeted cancer therapies and their results.
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PMID:Targeted cancer therapies. 1574 38

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.
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PMID:Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy? 1599 49

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder. We report the second family to date with a germline point mutation in exon 17 of the KIT gene that leads to substitution of aspartic acid at position 820 with tyrosine (D820Y). One or more GISTs was documented in three generations of this kindred, and there was associated hyperplasia of the interstitial cells of Cajal (ICC). One affected family member complained of dysphagia and another suffered small intestinal diverticulosis with perforation, which may represent additional consequences of ICC hyperplasia. Diffuse and nodular ICC hyperplasia associated with the latter family member's small intestinal diverticulosis is illustrated, providing supportive functional and morphologic evidence for the ICC being the cell of origin of GISTs. Skin hyperpigmentation was not observed. Analysis of a 17-cm malignant GIST in the index patient revealed that it was hemi/homozygous for the germline D820Y mutation, indicating loss of the remaining wild-type KIT allele with tumor progression. Two smaller lesions from this patient were heterozygous for the mutation. This phenomenon has been observed in up to 8% of sporadic malignant GISTs but has not been documented in familial disease.
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PMID:Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features. 1632 43

On January 26, 2006, sunitinib (Sutent) received regular approval as monotherapy for the treatment of patients with gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec). Time-to-tumor progression (TTP) of sunitinib-treated patients was superior to that of placebo-treated patients. Median TTP of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (p < .0001). Partial responses were observed in 6.8% of sunitinib-treated patients and no placebo-treated patients. Sunitinib also received accelerated approval on January 26, 2006, as monotherapy for treatment of advanced renal cell carcinoma (RCC). In two single-arm trials of sunitinib in patients with metastatic RCC, partial responses were observed in 25.5% (95% confidence interval [CI], 17.5, 34.9) and 36.5% (95% CI, 24.7, 49.6) of patients. Median response durations in the two trials were 27.1 weeks (95% CI, 24.4, incalculable) and 54 weeks (95% CI, 34.3, 70.1). Treatment-emergent adverse events in sunitinib-treated patients included diarrhea, mucositis, skin abnormalities, altered taste, electrolyte abnormalities, hypertension, and diminution in left ventricular ejection fraction. Cardiac safety of sunitinib in patients with preexisting cardiac abnormalities remains unknown. Based on nonclinical findings, physicians prescribing sunitinib should monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection. Caution should be exercised when administering sunitinib in combination with known CYP3A4 inducers or inhibitors.
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PMID:Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. 1722 5

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs range from benign indolent neoplasms to highly malignant sarcomas. Gain-of-function mutations of tyrosine kinase receptors, KIT or PDGFRA, have been identified in most GISTs. In this study, we report 36 GIST patients whose tumors had homozygous KIT exon 11 mutations detected by direct sequencing of PCR products. Loss of heterozygosity in KIT locus and other chromosome 4 loci were documented in majority of these tumors. However, fluorescence in situ hybridization with KIT locus-specific probe and chromosome 4 centromeric enumeration probe showed no evidence of KIT hemizygosity in a majority of analyzed cases. These findings are consistent with duplication of chromosome 4 with KIT mutant allele. Homozygous KIT exon 11 mutations were found in 33 primary tumors and 7 metastatic lesions. In two cases, shift from heterozygosity to homozygosity was documented during tumor progression being present in metastases, but not in primary tumors. Among primary GISTs, there were 16 gastric, 18 intestinal and 2 from unknown locations. An average primary tumor size was 12 cm and average mitotic activity 32/50 HPFs. Out of 32 tumors 29 (90.6%) with complete clinicopathologic data were diagnosed as sarcomas with more than 50% risk of metastatic disease, and 26 of 29 patients with follow-up had metastases or died of disease. An average survival time among pre-imatinib patients, who died of the disease was 33.4 months. Based on these findings, we conclude that presence of homozygous KIT exon 11 mutations is associated with malignant course of disease and should be considered an adverse prognostic marker in GISTs.
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PMID:Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors. 1843 12

Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial neoplasm of the gastrointestinal tract and show a predilection for the stomach. Most are detected because of symptoms, but some are incidental findings at autopsy or surgery for other reasons. Incidental GISTs tend to be smaller at diagnosis, but even small (<1 cm) GISTs have been shown to harbor activating KIT mutations at rates similar to advanced GISTs. However, the prevalence and characteristics of small GISTs in surgical resections of the esophagogastric junction (EGJ) remains unclear. We studied 150 esophagogastric resections for esophageal or EGJ carcinomas (100 with preoperative chemoradiation and 50 untreated cases) that had been extensively embedded for histologic examination (mean 30 sections/case). Number, size, morphology, and location of all GISTs and leiomyomas were recorded. All potential GISTs were evaluated with CD117 and CD34 immunohistochemistry, and a subset (35) leiomyomas with smooth muscle actin, desmin, and CD117. We found 18 incidental GISTs in 15 of 150 (10%) patients; 3 patients harbored 2 separate lesions. Prevalence of GIST was identical in treated (10 of 100) and untreated (5 of 50) cases. All (100%) showed positivity for both CD117 and CD34 and all were of spindle cell morphology. Lesions ranged from 0.2 to 3.0 mm in size (mean 1.3 mm). Eight (44%) were based in the outer muscularis propria, 7 (39%) in inner muscularis, and 3 (17%) between the muscle layers. The lesions tended to cluster near the EGJ, with 8 (44%) on the gastric side, 9 (50%) on the esophageal side, and 1 (6%) undetermined owing to overlying ulceration. Leiomyomas were even more common than GIST, occurring in 47% of patients (44% of treated and 52% of untreated, P=0.39), with a mean of 3 leiomyomas per patient (range 1 to 13) and mean size of 1.7 mm (range 0.2 to 12 mm). Unlike colorectal leiomyomas, most (91%) EGJ leiomyomas were located in the inner muscularis propria and only rarely (1%) in muscularis mucosa. These results suggest that GIST and leiomyoma are common incidental "seedling" lesions of the EGJ, found in 10% and 47% of patients undergoing surgery for esophageal carcinoma. The common occurrence of microscopic GISTs compared with the rarity of clinically manifest and malignant esophagogastric GISTs suggests that additional genetic or epigenetic alterations must happen for neoplastic progression.
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PMID:"Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. 1805 18


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